In Vitro Testing of Trichomonas vaginalis Drug Susceptibility: Evaluation of Minimal Lethal Concentrations for Metronidazole and Tinidazole That Correspond With Treatment Failure.

BACKGROUND: The only drugs approved by the US Food and Drug Administration for oral treatment of trichomoniasis belong to the 5-nitroimidazole group. Most individuals infected with Trichomonas vaginalis can be cured with a standard treatment of metronidazole or tinidazole, but it is estimated that more than 159,000 people fail treatment each year. Although a minimal lethal concentration (MLC) corresponding to treatment failure has been reported for metronidazole, the MLC for tinidazole associated with treatment failure has not been determined. We conducted a study using T. vaginalis isolates from women with reported treatment success or failure to determine these values. METHODS: We measured MLCs of 47 isolates obtained from women who had failed metronidazole treatment, 33 isolates from women who had failed tinidazole treatment, and 48 isolates from women successfully cured with metronidazole. The cutoff was calculated as the 95th percentile of MLCs of susceptible isolates for each drug. RESULTS: Our data confirmed that the MLC previously associated with metronidazole treatment failure is ≥50 µg/mL and identified the MLC associated with tinidazole treatment failure as ≥6.3 µg/mL. For metronidazole, the agreement between laboratory result and treatment outcome was 93.7%; for tinidazole, this agreement was 88.9%. CONCLUSIONS: The T. vaginalis susceptibility assay is useful for determining whether 5-nitroimidazole treatment failure in persons with trichomoniasis can be attributed to drug resistance. These results are useful for establishing interpretive guidance of test results, and MLC levels can help guide appropriate patient treatment.

US Regional Changes in Racial/Ethnic Disparities in HIV Diagnoses Among Women in the United States, 2012 and 2017.

Racial/ethnic and geographic disparities in HIV diagnosis rates exist among women in the United States. Black/African American women are disproportionately affected; rates are highest in the South and Northeast. Monitoring progress towards eliminating disparities in HIV diagnosis rates among women is a national HIV prevention goal. To illustrate the performance of different measures of disparities, we compared 2012 and 2017 HIV diagnosis rates among adult and adolescent females by race/ethnicity and geographic region. We used HIV surveillance data for diagnoses and five absolute and three relative measures of disparity. The absolute disparity decreased in each region; the relative disparity decreased with the exception of one measure in the Northeast and South. Despite progress, disparities in HIV diagnosis rates among women remain. Appropriate strategies to measure progress and contextualize findings are needed.

Social and Structural Factors Associated with Sustained Viral Suppression Among Heterosexual Black Men with Diagnosed HIV in the United States, 2015-2017.

This paper describes sociodemographic, sexual risk behavior, and clinical care factors associated with sustained viral suppression (SVS) among heterosexual Black men with diagnosed HIV in the US. Sample was 968 men, 2015-2017 cycles of Medical Monitoring Project. We used prevalence ratios and a multivariable logistic regression model to identify independent predictors of SVS. About 9% of sexually active men had sex that carries a risk of HIV transmission. Nearly 2/3 lived at or below the poverty level, 13% were under or uninsured, 1/4 experienced food insecurity and 15% reported recent homelessness. About 26% were not engaged in HIV care, 8% not currently taking antiretroviral therapy (ART) and 59% had SVS. Among men taking ART, care engagement and adherence were the only significant independent predictors of SVS. Efforts to increase VS should focus on increasing ART use, care engagement, and ART adherence, and include strategies that address the social and structural factors that influence them.

Disparities in Incidence of Human Immunodeficiency Virus Infection Among Black and White Women - United States, 2010-2016.

Incident human immunodeficiency virus (HIV) infections among adolescent females and women declined during 2010-2016, with the largest decrease (21%) occurring among black women (1). However, in 2016, although black women accounted for 13% of the U.S. female population, 60% of new HIV infections among women were in black women, indicating persisting disparities (1). CDC used the population attributable proportion (PAP) disparity measure to describe the proportional decrease in HIV infection among black and white women combined that would be realized if the group with the higher rate (blacks) had the same rate as did the group with the lower rate (whites) (2). Analyses indicated that an estimated 3,900 of 4,200 (93%) incident HIV infections among black women in 2016 would not have occurred if rates were the same for black and white women. The PAP disparity measure decreased from 0.75 in 2010 to 0.70 in 2016, suggesting that if incidence rates for black women were the same as those for white women, the annual number of incident HIV infections among black and white women would have been 75% lower in 2010 and 70% lower in 2016. Continued efforts are needed to identify and address social and structural determinants associated with HIV-related disparities to eliminate these disparities and decrease HIV incidence among black women.

Psychological and social determinants of health, antiretroviral therapy (ART) adherence, and viral suppression among HIV-positive black women in care.

Black women are disproportionately affected by HIV, accounting for 61% of women diagnosed in 2016. Black women with HIV are less likely to be adherent to antiretroviral therapy (ART) and virally suppressed compared to women of other racial/ethnic groups. We analyzed 2013-2014 data from 1703 black women patients in the Centers for Disease Control and Prevention's Medical Monitoring Project to examine whether select psychological and social determinants of health (SDH) factors were associated with ART adherence and viral suppression. We calculated weighted estimates and used multivariable logistic regression with adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) to examine correlates of ART adherence and viral suppression. Women who had not been incarcerated in the past 12 months (aPR = 1.24; CI: 1.04-1.48) and had not experienced discrimination in a health care setting since their HIV diagnosis (aPR = 1.06; 1.00-1.11) were slightly more likely to be adherent to ART. Women who lived above the federal poverty level were more likely to be virally suppressed during the past 12 months (aPR = 1.09; CI: 1.01-1.18). More research is warranted to identify the best strategies to create health care settings that encourage black women's HIV care engagement, and to address other key SDH and/or psychological factors.

Parents' Strategies to Support Mealtime Participation of Their Children With Autism Spectrum Disorder.

OBJECTIVE: We identified and described the strategies parents use to support the mealtime participation of their child with autism spectrum disorder (ASD). METHOD: Twelve families with children with ASD (ages 2-7 yr) participated in videotaped mealtime observations. Qualitative content analysis was used to identify strategies families used to facilitate participation. RESULTS: Six categories were identified: (1) parent intervening and ignoring, (2) meal preparation and adaptability, (3) play and imagination, (4) distractions, (5) positive reinforcements, and (6) modeling. Props-common child objects that support the child's mealtime participation-were used in the context of multiple strategies. In addition, increased parental vigilance emerged as an important component of all family mealtimes. CONCLUSION: Families used multiple strategies within and across mealtimes, highlighting the individualistic nature of feeding challenges. Understanding parent mealtime strategies allows for further investigation into the efficacy and development of intervention strategies to promote mealtime participation of children with ASD.

Ternary complex of human RORγ ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment.

Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.

Testing our FAITHH: HIV stigma and knowledge after a faith-based HIV stigma reduction intervention in the Rural South.

Eliminating racial/ethnic HIV disparities requires HIV-related stigma reduction. African-American churches have a history of addressing community concerns, including health issues, but may also contribute to stigma. We developed and pilot tested a faith-based, anti-stigma intervention with 12 African-American churches in rural Alabama. We measured HIV-related stigma held by 199 adults who participated in the intervention (individual-level) and their perception of stigma among other congregants (congregational-level). Analyses of pre- and post-assessments using a linear mixed model showed the anti-stigma intervention group reported a significant reduction in individual-level stigma compared with the control group (mean difference: -.70 intervention vs. -.16 control, adjusted p < .05). Findings suggest African-American churches may be poised to aid HIV stigma-reduction efforts.

Developing FAITHH: Methods to Develop a Faith-Based HIV Stigma-Reduction Intervention in the Rural South.

Human immunodeficiency virus (HIV) disproportionately affects Blacks/African Americans, particularly those residing in the southern United States. HIV-related stigma adversely affects strategies to successfully engage people in HIV education, prevention, and care. Interventions targeting stigma reduction are vital as additional tools to move toward improved outcomes with HIV prevention and care, consistent with national goals. Faith institutions in the South have been understudied as partners in HIV stigma-reduction efforts, and some at-risk, Black/African American communities are involved with southern faith institutions. We describe the collaborative effort with rural, southern faith leaders from various denominations to develop and pilot test Project Faith-based Anti-stigma Initiative Towards Healing HIV/AIDS (FAITHH), an HIV stigma-reduction intervention that built on strategies previously used with other nonrural, Black/African American faith communities. The eight-module intervention included educational materials, myth-busting exercises to increase accurate HIV knowledge, role-playing, activities to confront stigma, and opportunities to develop and practice delivering a sermon about HIV that included scripture-based content and guidance. Engaging faith leaders facilitated the successful tailoring of the intervention, and congregation members were willing participants in the research process in support of increased HIV awareness, prevention, and care.

Changes in the Disparity of HIV Diagnosis Rates Among Black Women - United States, 2010-2014.

In 2015, black women represented 61% of human immunodeficiency virus (HIV) diagnoses among women (1). HIV diagnosis rates among women declined during 2010-2014 (1); however, whether the decline resulted in a decrease in the disparities between black women and Hispanic and white women was unknown. To assess whether a change in disparities occurred, CDC used three different measures of disparity: 1) the absolute rate difference (the difference between the group with the lowest rate and the group with the highest rate) (2); 2) the diagnosis disparity ratio* (the ratio of the difference between the group rate and the overall population rate to the overall rate); and 3) the Index of Disparity (the average of the differences between rates for specific groups and the total rate divided by the total rate, expressed as a percentage) (3). The absolute rate difference between black women and white women decreased annually, from 36.9 in 2010 to 28.3 in 2014. The diagnosis disparity ratio for black women decreased from 1.7 in 2010 to 1.2 in 2014. The Index of Disparity increased during 2010-2011, and then decreased each year during 2012-2014. Although disparities still exist, these findings indicate improvement. Expanding access to biomedical and behavioral interventions and research guided by social and structural determinants frameworks could close the remaining gap.

Augmented Renal Clearance Using Population-Based Pharmacokinetic Modeling in Critically Ill Pediatric Patients.

OBJECTIVES: The objectives of this study were to: 1) evaluate the prevalence of augmented renal clearance in critically ill pediatric patients using vancomycin clearance; 2) derive the pharmacokinetic model that best describes vancomycin clearance in critically ill pediatric patients; and 3) correlate vancomycin clearance with creatinine clearance estimated by modified Schwartz or Cockcroft-Gault. DESIGN: Retrospective, two-center, cohort study from 2003 to 2016. SETTING: Clinical drug monitoring services in the PICUs at two tertiary care, teaching hospitals. PATIENTS: Children from 1 to 21 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Identify patients with augmented renal clearance (vancomycin clearance ≥ 130 mL/min/1.73 m used as definition of augmented renal clearance). Derive final population-based pharmacokinetic model and estimate individual patient pharmacokinetic parameters. Compare estimated glomerular filtration rate (modified Schwartz or Cockcroft-Gault depending on age < or ≥ 17 yr) with vancomycin clearance. Augmented renal clearance was identified in 12% of 250 total subjects. The final population-based pharmacokinetic model for vancomycin clearance (L/hr) was 0.118 × weight (e). Median vancomycin clearance in those with versus without augmented renal clearance were 141.3 and 91.7 mL/min/1.73 m, respectively (p < 0.001). By classification and regression tree analysis, patients who were more than 7.9 years old were significantly more likely to experience augmented renal clearance (17% vs 4.6% in those ≤ 7.9 yr old; p = 0.002). In patients with augmented renal clearance, 79% of 29 had vancomycin trough concentrations less than 10 µg/mL, compared with 52% of 221 in those without augmented renal clearance (p < 0.001). Vancomycin clearance was weakly correlated to the glomerular filtration rate estimated by the modified Schwartz or Cockcroft-Gault method (Spearman R = 0.083). CONCLUSIONS: Augmented renal clearance was identified in one of 10 critically ill pediatric patients using vancomycin clearance, with an increase of approximately 50 mL/min/1.73 m in those with augmented renal clearance. As augmented renal clearance results in subtherapeutic antibiotic concentrations, optimal dosing is essential in those exhibiting augmented renal clearance.

Targeting Mycobacterium tuberculosis topoisomerase I by small-molecule inhibitors.

We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the M. tuberculosis and M. smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.

An integrated suite of modeling tools that empower scientists in structure- and property-based drug design.

Structure- and property-based drug design is an integral part of modern drug discovery, enabling the design of compounds aimed at improving potency and selectivity. However, building molecules using desktop modeling tools can easily lead to poor designs that appear to form many favorable interactions with the protein's active site. Although a proposed molecule looks good on screen and appears to fit into the protein site X-ray crystal structure or pharmacophore model, doing so might require a high-energy small molecule conformation, which would likely be inactive. To help scientists make better design decisions, we have built integrated, easy-to-use, interactive software tools to perform docking experiments, de novo design, shape and pharmacophore based database searches, small molecule conformational analysis and molecular property calculations. Using a combination of these tools helps scientists in assessing the likelihood that a designed molecule will be active and have desirable drug metabolism and pharmacokinetic properties. Small molecule discovery success requires project teams to rapidly design and synthesize potent molecules with good ADME properties. Empowering scientists to evaluate ideas quickly and make better design decisions with easy-to-access and easy-to-understand software on their desktop is now a key part of our discovery process.

Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA, a eukaryotic type II topoisomerase poison.

m-AMSA, an established inhibitor of eukaryotic type II topoisomerases, exerts its cidal effect by binding to the enzyme-DNA complex thus inhibiting the DNA religation step. The molecule and its analogues have been successfully used as chemotherapeutic agents against different forms of cancer. After virtual screening using a homology model of the Mycobacterium tuberculosis topoisomerase I, we identified m-AMSA as a high scoring hit. We demonstrate that m-AMSA can inhibit the DNA relaxation activity of topoisomerase I from M. tuberculosis and Mycobacterium smegmatis. In a whole cell assay, m-AMSA inhibited the growth of both the mycobacteria.

Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Cis-amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase.

Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.

Unintentional ingestion of putative delta-8 tetrahydrocannabinol by two youth requiring critical care: a case report.

BACKGROUND: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid from the cannabis plant that can be synthetically converted from cannabidiol (CBD). Most states permit the full or restricted sale of hemp and hemp-derived CBD products, and therefore, delta-8 THC products are on the rise. Delta-8 THC consumption can cause intoxication. Products are often sold in edible form and occasionally in packaging that appears similar to candy. Clinical presentations for delta-8 THC ingestions are understudied and may differ from those described for delta-9 THC ingestions. CASE PRESENTATION: This case report describes unintentional ingestions of putative delta-8 THC by two pediatric patients that results in admission to the pediatric intensive care unit. The ingestions were of putative delta-8 THC infused product that resembled popular candies. Both patients developed periods of bradypnea with continued intermittent periods of agitation. Medical intervention included observation, noninvasive positive pressure ventilation via high flow nasal cannula, and intubation-but was not needed for both patients. Although family noted ongoing irritability for the patients, both were discharged approximately 45 h after ingestion. Delta-8 THC ingestion is reliant on self-report. CONCLUSIONS: As the availability of delta-8 THC increases, along with associated pediatric exposures, it is imperative for health care providers to quickly recognize and provide adequate treatment. While there is no specific antidote for THC intoxication beyond supportive care, providers can play an important role in prevention by educating parents and guardians on safe cannabis storage and by documenting cases for adverse event monitoring.

Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Examining interest in secondary abstinence among young African American females at risk for HIV or STIs.

Sexually active African American females are at increased risk for acquiring HIV or STIs. However, some reduce their risk by abstaining from sex for various periods of time following initiation, a practice known as secondary abstinence. Although this may be a valuable mechanism for reducing HIV or STI rates in this population, little is known about those interested in secondary abstinence. Baseline data were obtained from a sample of African American adolescent females, ages 14-20 years, prior to participation in an HIV-risk reduction intervention trial (N = 701). Differences in individual-level and interpersonal-level factors, as well as sociodemographic variables were examined between participants who reported strong interest in secondary abstinence and those who did not. 144 (20.5%) participants reported strong interest in secondary abstinence. Young women with strong interest in abstinence had higher odds of reporting a history of STIs and feeling negative emotions following sex because of their religious beliefs. They also had higher odds of believing their partner may be interested in abstaining and being less invested in their relationship with their main partner. Additionally, adolescents reported less interpersonal stress and more social support. African American females who are interested in practicing secondary abstinence and those who are not differ in their sexual health education needs. Findings from this study characterizing young women interested in secondary abstinence can help researchers provide more targeted health education by identifying those who may be more responsive to abstinence-promoting messages.

Pilot Testing a Brief Partner-Inclusive Hybrid Intervention for Perinatal Mood and Anxiety Disorders.

The necessity of hybrid and more accessible options for perinatal mood and anxiety disorders (PMADs) has taken on increased urgency in the wake of the COVID-19 pandemic and its lasting impacts. In the New Family Wellness Project (NFWP), participants engage in a hybrid in-person and teletherapy six-session intervention for new parents early in their postpartum period. This small, phase 1 clinical research examined early outcomes of the NFWP's cognitive behavioral intervention on adverse mental health outcomes (i.e., perinatal depression and anxiety, overall mental illness symptoms) and adaptive outcomes and protective factors (i.e., relational health, social support, flourishing, self-efficacy). Despite a small sample size (N = 12), paired t-tests yielded significant effects for improvements in mental health symptoms at posttest, as well as marginally significant improvements in postpartum anxiety and self-efficacy. Findings suggest the brief, partner-inclusive, hybrid intervention shows promise for further study. Lessons learned from this small phase 1 clinical study and recommendations for revising the intervention prior to future trials are discussed.